Figure 17-1. (A) Aristotle; (B) young Darwin; (C) young Wallace. (A) Statue in Vienna art museum, copied from (Bowder 1982), (B) 1840 painting by George Richmond.

explanatory power. Among our points is that one can accept Darwin and Wallace's deep insight, yet need not overly or uncritically invoke the single force of systematic natural selection as we try to understand the evolution of life.

Before there was much formalized history and essentially no paleontology—no sense of great time depth in the affairs of our planet—a static view of the nature of the relationships among the different forms of life on Earth was not just natural but probably the best supportable one (although there were dynamic cosmologies even among the ancient Greeks). In a static worldview, it was easy to group similar-looking animals, like different types of fish or birds or butterflies, and to infer that they have a relationship with each other.

Aristotle is widely credited with expressing the first systematized biology, which included the notion of a qualitative scala naturae (natural ladder, scale, or order of all life), the natural ranking of beings according to their relationships, and considering them in order. In a classic book, Arthur Lovejoy (Lovejoy 1936) traced the history by which this idea, which came to be called the Great Chain of Being, was established in Western culture; mainly, it was fitted into our biblically based cosmology with a point of origin at the Creation. In most Western versions, of course, this is a linear hierarchy with humans at the top (but under God) and the rest of the chain in service to us.

However, evidence was accumulating into the 19th century that the Earth was older and organic beings were not so static as had once been thought. Discoveries in geology, agricultural breeding, geographic distribution of forms found by world exploration, and a growing appreciation of the meaning of fossils all led to the burgeoning realization that species had changed over time. Darwin and Wallace provided a very general process that could account in principle for this dynamic history and connect the entire living world—plant and animal—into a single phenomenon.They stressed selection, but probably as important was that time and connectedness through common ancestry became key variables in biological explanation.

Biology has not abandoned a great chain of being, but we account for it in a new and less arbitrary, materially more testable way. And, taking organisms past and present, the chain has been rearranged. The evolutionary process leads to diversifying rather than linear connectedness, and does not imply that the tips of one branch are qualitatively better than those of another, only that their ancestors were successful in their own times and relative to their local situations. Despite this, however, an informal notion of progress, basically of a qualitative hierarchy in nature, is surprisingly persistent in our culture and in biology itself (Ruse 1996), even though it is manifestly true that simple organisms still thrive today. The notion of progress is more than a human conceit; it leads to a kind of tacit general inference of perfection and tightness of adaptation in the world.

The new evolutionary worldview was wondrously reaffirmed during the 20th century in a totally unpredicted way. Biologists adopted the molecular reduction-ism of the physical sciences and used it as the framework for looking inside organisms, to show that their parts, including their genes, had their own reality as biological entities, and were also connected in an historical way and that this was related to the general pattern of connectedness of whole organisms. Rather than a great chain of static being, what we see now is all organisms and their multilayered internal constituents, interdependent today and linked through a three- or four-billion-year-old continuum of interwoven connections: a Great Chain of Beings.

It is worth quoting Darwin's famous reflection on the grandeur of life by which he closed Origin of Species in 1859:

It is interesting to contemplate an entangled bank, clothed with many plants of many kinds, with birds singing on the bushes, with various insects flitting about, and with worms crawling through the damp earth, and to reflect that these elaborately constructed forms, so different from each other, and dependent on each other in so complex a manner, have all been produced by laws acting around us. These laws, taken in the largest sense, being Growth with Reproduction; inheritance which is almost implied by reproduction; Variability from the indirect and direct action of the external conditions of life, and from use and disuse; a Ratio of Increase so high as to lead to a Struggle for Life, and as a consequence to Natural Selection, entailing Divergence of Character and the Extinction of less-improved forms. Thus, from the war of nature, from famine and death, the most exalted object which we are capable of conceiving, namely, the production of the higher animals, directly follows. There is grandeur in this view of life, with its several powers, having been originally breathed into a few forms or into one; and that, whilst this planet has gone cycling on according to the fixed law of gravity, from so simple a beginning endless forms most beautiful and most wonderful have been, and are being, evolved.

This "vision statement" is interesting in ways that are perhaps unappreciated. Much food for thought is here, including mistakes relative to the currently prevailing view. Darwin uses the image of an "entangled" bank, of life interdependent, brought about through common "laws" that we still see "acting around us." He states the fundamental core principles we outlined in Chapter 1. He keeps open the possibility that life may have derived from more than one founding form—and we have seen some evidence of a reticulated rather than simple Tree of Life, perhaps particularly early on before the highly structured cell that we know today stabilized as a basic form (Chapter 2). Darwin stresses the divergent nature of the process, but his view is somewhat lamarckian ("variability from ... use and disuse"). His evolutionary theory was so powerful and represented so deep a truth that it withstood incorrect notions even about core elements such as the nature of heredity and the age of the Earth.

Darwin's is largely a metaphor of the world as a Hobbesian war of all against all, driven by overpopulation relative to resources. Historians have suggested that his view of life was colored by his being a wealthy member of the world's Imperial power. This predisposition is said to be reflected in Darwin's regular allusion to the struggle for survival as an essentially deterministic and gradual view of life driven by laws as ineluctable as those of physics. Systematically, the better and more powerful are destined to prevail; the law of the jungle is the law of nature. Whether or not Darwin's view is based on his wealth and privilege in the British Empire, that view is the prevailing one today.

When Mendel demonstrated the discrete nonblending nature of heredity—that heredity was a natural "atomic" process of some kind—he opened an important door to further the understanding of evolutionary mechanisms. A century of intense work identified the molecules involved and demonstrated that they were inherited and modified in ways that could be fitted to the general processes leading to accumulated biological diversity that Darwin and Wallace had invoked. The result has been a set of broad, general principles, formalized as population genetics, which are applied universally to the evolution of life. That is what makes the work of Darwin, Mendel, Wallace, and other founders of modern biology so powerful.

In this book, we have looked at how evolution and genetics apply to a selection of different kinds of biological processes that exemplify the basic aspects of biological complexity. These include:

Figure 17-2. An entangled bank. Central Pennsylvania, USA. Photograph by E.Weiss.

1. how the largely prespecified complex forms of a differentiated organism start from simple beginnings like a single cell;

2. how complex differentiated entities can reproduce;

3. how the components within an organism communicate to bring about a unity of coordinated functions;

4. how organisms detect a variety of external conditions that cannot be pre-specified but that are important to their life ways; and

5. how the latter information is interpreted and translated into responses.

We have discussed how a set of simple principles stated by Darwin and Wallace, a few others that supplement their theory, and a modest toolkit of genetic mechanisms can account for the diverse world of biological complexity and achievement. Some of the principles are not typically included as formal premises of biological theory, but including them helps integrate a unified and more complete understanding of the great chain of beings in the world today.

Darwin's Basic Postulates

For most purposes, all living forms can be viewed as descendants of a single origin on Earth. A "single origin" for all life does not mean a single original molecule, species, trait or gene. All have their own individual, partially independent nested origins over time. Rather, biology posits a single set of starting conditions and that the essence of the system, once begun, did not receive meaningful extraterrestrial contributions (even if, say, amino acids continue to rain down on Earth) and did not keep originating (and in particular, required no spontaneous creation of complex organisms). In many ways including ancient or even occasional modern horizontal gene transfer, sexual reproduction, and recombination, life is as interconnected today by biological processes as it is by a unitary ancestry, and the former is ultimately because of the latter. If other forms of biological activity—for example, those not relying on DNA or RNA or protein coding—existed back at the beginning, they have become extinct without leaving a trace that we recognize today. They need not be considered to understand how biology works today, but it is worth noting that if such other orders did exist, our assumption that the coalescent structure of all life today reconstructs the origin of life, will blind us to them.

Biological information that is replicated across the generations of reproduction can accumulate a trace of its past, as we see in DNA. This is due to the modular, slowly mutating nature of DNA but is not a formal necessity of darwinian evolution per se. This is clearly so, as Darwin's ideas of genes were largely wrong. Many aspects of a cell are specific to each organism and are inherited but do not bear such a trace; examples are the particular mix of minerals, salts, pH, vitamins, minerals, and so on. These are inherited in the fertilized cell by which life begins but do not retain a permanent kind of information the way genes do. Still this illustrates a legitimate and important point about primary versus secondary causation in life: is it DNA or cytoplasm? Chickens or eggs? This is not a conundrum at all: the answer is both. Eggs are continuations of chickens, a chain of cell division going back billions of years.

If we do not force ourselves to be constrained by an overly rigid definition of inheritance as strictly applying to genes, similar statements are true of aspects of life that are inherited in other ways (Chapter 3). Indeed, some are inherited in a lamar-ckian fashion; for example, behaviors learned or traits acquired in life that are transmitted to offspring, like local microenvironments, birds' nests, and aspects of verbalization. Of course, cultural inheritance is vital to human survival, and its accumulated sophistication makes possible our social and technical complexity—that makes us seem qualitatively different and superior to all other organisms. But a human stripped naked and dumped alone deep in a wilderness would be a laughable King of Life. If John Milton (Paradise Lost) is any guide, Adam and Eve were created with a house, plantation, and cookware. Culture is inherent in what differentiates us from other animals, not a trivial add-on unrelated to our evolution, and something similar is true of most if not all animals. Of course, the inheritance of acquired characters we are referring to has no implication of inner drive toward some long-term goal, although human culture is probably more truly Lamarckian in that respect than almost anything else in the living world.

Malthusian population pressure was an important stimulus for Darwin and Wallace, and is important in life but not necessary to evolution. Phenotypic change could in principle occur in a population that did not suffer from overreproduction, for example, if all individuals had equal chances of reproducing (that is, change by drift). But if more individuals exist at any time than their source of nutrients or propagation can support, and if relative success depends on heritable information, and ifthat information relates to form, then whatever the cause, there will be change of form. Darwin and Wallace had the great insight that if there was a systematic favoring of a particular subset of competing forms, that could produce particular kinds of adaptation, and natural selection became a transforming concept. But population pressure does not guarantee by itself that there will be this kind of adaptation, and we know that differential reproduction is heavily affected by chance. We also have seen in Chapter 2 and elsewhere ways in which the fact or nature of adaptation, always viewed after the fact, can be illusory. All organisms are the descendents of an unbroken chain of nearly four billion years of successfully adapted ancestors—whether or not they had the highest fitness, as measured by population genetics, among their respective peers.

The basic darwinian principles not only provide a logically coherent explanation of how complex evolution can occur, but predictions from this reasoning are borne out regularly in new data that were not used to develop the theory. Examples are the statistical correlation of DNA sequence differences with times of separation among species, and the lower level of variation in DNA sequence affected by selection. Although the theory does not enable us to predict the specifics, the general kind of predictive power of evolutionary biology constitutes a convincing demonstration that the notions are compatible with a large body of data, and that is the most we can ask of any science.

Evolutionary theory allows fewer "bits" of information to account for at least some aspects of life than their complete description and enumeration. However, there is a danger that a convincing theory becomes a constraining ideology, with vested interests that resist dissent just as in any other ideology, and in some hands this has occurred in biology. Ideology fetters thinking, and this is important to avoid as we try to understand how life has evolved because there really are a few problems, of incompleteness if not also of stress, with the elements of the theory of Darwinian evolution.

Some Additional Principles: Modularity and Sequestration

Darwin's notion of divergence of character is empirical rather than logically necessary. Competition by itself does not imply systematic or deterministic change of an adaptive nature. Even when it has a genetic basis, evolutionary theory does not claim to provide any guide as to how adaptation will occur, only that it will. Nor does the theory say anything about the mechanisms by which complex traits come about in organisms. A few additional principles help fill those holes.

The DNA/RNA coding system, based on complementary base pairing jg between nucleotides, and the nature of protein-protein interaction speci- Jffk ficity are principles of evolution as it has happened on our planet. DNA Jm& base pairing provides a universal, modifiable system with historical memory that, once evolved, makes the rest of divergent evolution and adaptation relatively easy and plausible to understand. As has been said of cells, after they evolved the rest was easy—and is explicable in cellular terms. In many ways, after the RNA/DNA system, the rest can be explained in terms that relate to this system.

Everywhere in life the importance of modularity or segmentation is clear. From the modular nature of proteins and DNA, through cells, through perhaps the vast majority of the structures and systems of complex organisms, nature is composed of modules. This is immediately apparent as a fundamental characteristic of genes themselves. New genes could in principle arise by the incremental accretion of nucleotides to the ends of chromosomes until, by chance, they formed a valid coding unit that could be expressed, but they don't. The genome can be viewed as an assemblage of modular elements, including gene family members (each with internally replicated structures like exons, splice signals, and the like), replicated telomeres and centromeres, and regulatory elements.

This reflects billions of years of duplication events plus the evolution of short elements like enhancers by mutation in otherwise noncoding DNA. These processes result in genes connected together on chromosomes along with regulatory sequence, which allows for differentiation among cells, and which in turn allows for multi-cellular organisms. Indeed, life works the way it does fundamentally because genes are concatenated on chromosomes and thus fundamentally through modular organization that was made possible by this duplication history (something presciently seen, with relatively little data, by Ohno (Ohno 1970)). In retrospect, we can see the chemical ways in which mutation and erroneous replication lead to duplication of structures. Thus, duplication is a commitment made so early that it is now as fundamental as any other of the postulates of biological evolution as it happened on Earth.

Modular physical structures occur from cells on up and across all of life. They include direct repeats, as in hair or leaves, or modified repeats as in regionally differentiated vertebrae, digits, or limb segments or butterfly color spots. Physiological systems are similarly organized. They involve the interaction and differentiated use of the products of duplicated, differentiated gene families. From lipid and oxygen transport to neurotransmission, transcription regulation, olfaction, immune response, selective sampling of frequencies in the light spectrum, hormonal signaling, ion channel formation, and most else, this is the molecular nature of cells and organisms. In fact, the core constituents of life themselves (amino acids, nucleic acids, lipids) are modular branches of the core biochemical energy-processing system of life (Morowitz et al. 2000).

Gene duplication provides some of the wherewithal for repeti- - - ^ i-tive structures,but modular structures themselves consist of spatial ¿i';-',' H ^T or temporal repeats of patterns of similar gene expression rather ~ ' than literal duplicates of a separate set of genes for each module in the system. Here, replication, sometimes with modification, occurs via interacting combinations of products of gene families and results in spaced replicated zones of structure activation surrounded by inhibition zones. In the sense of scientific understanding, but also in the sense of the phenomenon itself, repetitive patterning as a process involves fewer "bits" to make something complex.

None of this works without extensive sequestration. Darwin knew that there were problems with his blending theory of inheritance, but the fundamental importance of nonblending applies at all levels of life. Life may have begun in a fluid soup of some sort, in which simple chemical reactions took place in public. But at some point billions of years ago, this changed, which explains differentiated life as we have seen it from the earliest fossils to the present. From the nonblending nature of DNA sequences (including codons, enhancers, and so on) to the origin of cells as ways to protect an accumulating repertoire of vital internal reactions in controlled isolation from the external environment, sequestration of biological elements allows them to differentiate, specialize, and interact.

Sequestration makes possible the discrimination of immune, visual, auditory, and olfactory signals. To the extent that signals from different receptors activate the same neuron, the organism cannot make specific discrimination as to the source (e.g., in nematode olfaction each cell expresses multiple receptor genes and, in some insects, brightness and color signals may merge in their path to the brain). Diffusible signals in development are by definition not sequestered for the very reason that their relative strength across a tissue field is presumed to carry the developmental information for local cells within the field. But the reception of these signals is sequestered in that there are distinct, separate receptors or binding proteins for each signal to be received and specifically recognized. The receiving cells must be sequestered so that they can develop independently, which is how such a uniform tissue field becomes differentiated.

Actually, sequestration has led to life being a network of interactions among otherwise isolated elements. Divergence is important, but horizontal interaction (that is, among contemporary molecules, cells, organisms, and even species) is completely essential to organized life. Sequestration in many if not most instances is not or perhaps cannot be complete. Interactions are fundamental to development, homeostasis, reproduction, and even gene evolution (recombination, gene conversion, and gene regulation by trans factors acting on cis gene-regulatory elements). Complete sequestration would prevent that. And if hormones are diffusible signals within an organism, pheromones, flower color or odor, and ritual display or sound are examples of diffusible signals among organisms and species. In each case, the recipient has to be enabled to receive the signal, and we have seen many ways in which this happens; much of life depends on ligand-receptor binding to transfer information of diverse kinds in diverse ways.

Related to the notion of sequestration is the fact that most biological processes are contingent. This is implied by modularity, sequestration, and nested hierarchical organization because each new step in a process or stage of development is based on conditions at the time. However, it is the partial nature of sequestration that enables divergence to occur but not to isolate components completely. This is an important way in which the notion of cooperation in life is extremely important, to keep systems, organisms, species, and ecosystems integrated to varying degrees.

An Expanded View of the Role of Chance

Because we can always observe the current adaptation of a species, nothing prevents us from expressing (and, if we wish, believing) the idea that the adaptation is "remarkable" and "had" to have been molded by natural selection. But the after-the-fact nature of our observations means that this is a human judgment, and we are necessarily blinded to the nature of time periods far longer than our direct experience; we have to model them with some sort of law-like theory, often using the mathematics of population genetics because that captures general ideas in somewhat tractable form—abstract, but digestible.

A modified view actually makes Darwin's central idea of divergence from shared ancestry even more plausible: present-day adaptation does not in principle require a systematic, steady, or prescriptive selective environment. Chance is a frustration treated as a source of measurement noise in a science seeking deterministic highly predictive laws of nature, but chance has much more of a direct influence on life itself than is generally credited.

The difference between chance and selection largely depends on the parameters of the process, including population size and structure, intensity of selection and the like. The question as to whether there has been "enough" time for chance to have brought about given adaptation really rests on the general property that change happens faster when directed than when meandering. In this sense, as the estimated age of life moves backward (getting older), the role of chance via phenotypic drift and phenotypic substitution becomes more tenable in principle.

But since what is here is here because it has worked, and no specific thing had, a priori, to be here, the time question is a somewhat moot point, as explained in Chapter 2. Has there been enough time for R-genes or olfactory genes to evolve sufficient diversity? Is this even a meaningful scientific question? Of course there has been enough time, unless our most fundamental idea about a terrestrial, unitary origin of life is wrong. The more important issue is what mix of factors may have been responsible.

A highly deterministic view that assumes that selection is intolerant of variation, and highly prescriptive in nature is not necessarily accurate, and we know it is often inaccurate. In most of the examples we have covered in this book—from the constituents of cells on up— it would be difficult to argue, other than post hoc, that what exists today is actually optimized. Would one be able to say that about sex-determining mechanisms? If so, which ones? What about vision or olfaction or immunity? If these have been optimized, in what sense, and why are they so different, both among species and between individuals? What about people who type with two fingers rather than all ten? Daily life all around us is manifestly inefficient. Perhaps a better question is how prescriptive can we expect selection to be?

The answer seems clearly to be contextual. Optimizing or any other kind of tightly determining selection can certainly occur in principle, in the laboratory, or under the appropriately strong limiting conditions (like nutritional stress or the imposition of antibiotics or pesticides, but breeding experiments show that there are limits to what even artificial selection can accomplish). Nonetheless, although conditions for strong selection might occur, chance is always a factor in change from one generation to another. Phenotypic drift is a legitimate and logically plausible means of change. Humans are builders, and it seems difficult to understand that chance can play a role in what from our perspective seems clearly designed for its present adaptation. But accepting a greater role of chance relieves some of the need to construct specific post hoc selective scenarios that, no matter how attractive, often show exceptions and complications that must then have to be accounted for by caveats and additional explanations.

For most traits that we have discussed in this book, there is a diversity of standing variation. This applies to perceiving light or chemicals, defending against micro-bial attack, and even the essential phenomenon of sexual reproduction. These traits seem to have been shared by common ancestors of animals and plants, so their diverse forms today are one kind of evidence that nonspecificity of mechanism is important, not just a curious observation, and is a widespread if not fundamental characteristic of evolution.

Also as noted in Chapter 3 and elsewhere, change in the genetic basis of pheno-types can occur even when classical natural selection is taking place. Selection screens on phenotypes and does not "care" or detect how those are brought about. It works only indirectly on genes. This is a powerful protective mechanism, in that it allows for redundancy and alternative genetic pathways that may make survival and persistence more likely. Some core metabolic processes and highly specific communication via pheromones seem to have been rather tightly controlled even at the gene level, and may place deep constraints on evolution. However, as frequently demonstrated by gene knockout experiments in mice that fail to show the expected phenotypic effect or show it only in some background strains, even basic developmental systems that produce rather invariant phenotypes have buffered or alternative mechanisms. And some important functions, like olfaction, vision, and immunity, have specifically imprecise mechanisms that increase the chance of success: their sensitivity does not depend on the presence of one specific allele or gene.

Tolerance of variation is itself a survival mechanism, and every redundancy and imprecision is an opportunity for drift. It is in this sense wrong to think of variation as "noise" around some true signal (often called the "wild type") specified by selection. It is true that rabbits breed rabbits rather than mice, and this is certainly the result of genes. But the appearance of specificity in comparing species is at least in part an artifact of reproductive isolation. After long time periods, the variances around trait modes among related species may no longer overlap.

But within species there is always variation, and gene mapping studies and studies of allelic effects on most complex traits that have been looked at carefully bear this out. This is true of human and mammalian disease mapping, studies of yeast and bacteria, and natural and experimental observations in fruit flies, agricultural breeding, and so on. Many genes contribute allelic variation, generally of low individual penetrance, and there is phenogenetic equivalence. One cannot accurately predict the phenotype from knowledge of the genotype (except under favorable or highly constrained circumstances, or in a probabilistic sense). Similarly, and for related reasons, we usually cannot infer the underlying genotype from the observed phe-notype, and if we can't do that, natural selection—much blinder than we are because it only uses the one criterion of fitness—can't do it either.

An important lesson we have learned from experimental and observational studies of genotype-phenotype relationships is that they often depend on the population of inference; they are not universals (Lewontin 2000; Schlichting and Pigliucci 1998; Weiss and Buchanan 2003). Related to the presence of redundancy at any given time is the evolutionary consequence that selection can keep a trait or function around over evolutionary time while its underlying genetic basis or even its physical basis changes. We have described examples of phenogenetic as well as phenotypic drift. Phenotypes, by and large, are not inherent properties of genotypes, and this is even truer of fitness, and as we tried to stress early on, it can be a mistake to treat selective coefficients in that way.

One gets a rather different view of evolution from the perspective of the trait or organism, not the gene. However, this is more in line with what motivated Darwin and Wallace in the first place, and it has ironic implications. Genes may bear the information trace of the past, and organisms may typically develop from single cells and hence be genetically driven; however, if the trait rather than the gene is what selection maintains, the ephemeral trait may be more "real" or lasting in that sense than its underlying genetic basis.

This certainly does not imply that traits evolve without underlying genes. Nor does it imply that there is no conservation of mechanism. Indeed, we have seen throughout this book exceedingly deep conservation of at least some aspects of phenogenetic mechanisms. The role of Pax6 and opsins in vision across the animal world and extending even to algae and of genes inducing dorsoventral patterning between vertebrates and invertebrates are examples. But phenogenetic drift does occur and provides a view of evolution that is less imprisoned than reasoning that demands more causal genetic precision by selection need be.

Adaptive Evolution: Selection and Drift are a Continuum of Effects

There has long been debate about the relative prevalence of selection versus drift in evolution. In fact, these constitute a continuum. We discussed the key elements in the early chapters of this book. Genetic drift occurs when selective coefficients, s, equal zero (that is, the genotypes being considered have equal fitness). But this parameter is fundamentally context-dependent (it is defined as pertaining to peers within a population of inference). Unfortunately, this leads to a practical problem, because of the notorious difficulty in detecting selection in nature.

Even some of the most classic examples of selection such as related to the beaks of Darwin's famous Galapagos finches, or protective coloration associated with industrial melanism in peppered moths over the past two centuries, are not as clear as had been thought (Grant 1999; Grant and Grant 2002; Weiss 2002a). These are cases where the supposed selection probably is at least one of the important factors involved, and is probably a relatively strong force.

Instead of direct observation, we usually have to detect the effects of selection in a general way by comparing genomic sequence in various ways, and inferring that selection is responsible for the more stable aspects of the data. Thus, we infer that selection is responsible for the systematically lower observed variation in coding than in intronic DNA, or in regions of a gene showing more sequence conservation in one species than in another. Equating function with reduced variation is at least a little bit circular, but it generally corresponds with what we know of DNA function. It is this kind of analysis that led to the genetic load problem we discussed in Chapter 4, because while selection is so difficult to document in regard to genes on the ground, the statistical evidence for it is pervasive across the genome. It is not easy to account for how daily life can support the amount of selective loss required to maintain so many variation-constrained regions across the genome.

The most persuasive resulting generalization from this kind of population genetic approach to sequence variation is known as the "nearly neutral" view of evolution. As mentioned in Chapter 3, it seems that most of the time most selective coefficients are so small that the future fate of an allele is as much or more affected by drift than by the effects of selection (Ohta 1992).

Population genetic data have been showing things like this for a long time, but it is nonetheless common, if not usual, to see evolutionary explanations that equate present-day function with selective history. This often assumes steady, gradual selection as the causative agent and accepts the net result of selection as an adequate way to account for the local, day-to-day events that were actually responsible over evolutionary time and space. That verges on a kind of determinism that implies that what is here was destined in advance, and is in part a product of the adaptive illusion.

Despite this tendency, biologists are in unanimous agreement that this is an incorrectly teleological view. To account for complex evolution in a nonteleological way, we take from Darwin himself the assumption that complex traits got here through a series of intermediate precursors (sometimes called "exaptations") that had their own evolutionary reason for being. The usual reconstruction is to attribute selection to each such stage. The fossil record or comparative biology sometimes shows us what these earlier stages were, and sometimes we guess at what they may have been. Evolution is contingent in that changes from one stage to the next depended on selection among variation and by conditions that existed at the time, having nothing directly to do with what might happen in the future, and in that sense the model is one of "chance" evolution, even if selection is responsible all along the way.

However, as we noted in Chapter 3, our everyday experience trying to demonstrate selection in action today, tells us that these local stages probably were, in their time, typically not under intense selection. Slow evolution with small selective coefficients at any given point in turn means stepwise nearly-neutral evolution. This in turn implies that drift can be important if not predominant at many or even most stages of the process. Of course, there is no way or reason to rule out occasional bursts of more stringent selection, nor that at all points on the way selection may have truncated phenotypes that were out of bounds for their local conditions. But small s means the bounds were broad, and tolerant of variation, for example, culling only at the extremes and shaping variation, but only weakly.

This scenario allows phenotypic drift to apply to the incremental changes, allowing a much greater role for chance than in the usual view. Indeed, pushed to its extreme, it allows what we judge retrospectively to be highly molded and focused to be due instead largely to chance, both in the contingency and the drift sense. This general model of complex trait evolution is consistent with the combined action of natural and organismal selection, various levels of drift, the extensive evidence for nearly neutral evolution inferred directly from patterns of DNA variation, pheno-

genetic equivalence due to many loci affecting complex traits, the existence of standing variation in populations today in essentially all traits (indeed, the fuel for future evolution), the imprecision and "imperfection" of biological traits, the widely varying forms of traits even among related species (that the examples in this book clearly show), and the correlation between separation times and phenotypic differences.

This view is completely consistent with the genetic theory of evolution, though it does not over-invoke classical, gradual, steady selection. Its elements are all familiar. The most difficult thing is to shake the anthropic illusion and to allow something that is functional to have evolved largely by chance in a much deeper sense than we usually accept. But because selection and drift are themselves in many ways different points on a continuum of effects, between this view and one invoking selection more strongly, the differences are matters of scale and perspective, as is so often the case in science.

Some Additional Points

Watson and Crick characterized the basic nature of genes, which shows how the replication of chromosomes makes it possible for every cell in an organism to contain the entire inherited genome (except for somatic mutations). But this did not explain how cells with the same genome could produce a differentiated organism. We now know quite a lot about the way in which specific subsets of genes are activated in specific cellular contexts via cis-regulation using modular response elements in and around them. We have learned of other ways gene expression level is adjusted, including RNA interference, and quantitative effects of different numbers of copies of given enhancers, tolerance of variation in enhancer binding sequences, and the packaging or chemical modification of DNA near a gene that may affect transcription factor binding.

We have learned in recent decades of other sequence-based functions in DNA, including chromosome protection (telomeres), separation during cell division (centromeres), packaging (histone binding sites), and multiple RNA splicing to affect protein structure. These aspects of DNA sequence expanded the traditional meaning of the word "gene" from just protein coding to include these many additional functions. Others likely remain to be discovered. This changing understanding of the nature of the gene does not challenge the essential ideas in the genetic theory of evolution, which is based on the change in frequency of heritable variants, whatever their nature. But the diverse functions of DNA add richness to our understanding of evolution's mechanisms, and contribute to a more complete theory of evolution.

The function of many genes (perhaps most genes in complex organisms) involves regulating the expression of other genes, signaling, or other similar kinds of indirect function. Genes responsible for the final aspects of the traits—that is, the physical phenotypes of traditional evolutionary interest like morphology or behavior—are buffered from direct detection by selection by layers of causal interactions. Unlike specific proteins such as hemoglobin, most of these indirectly acting genes have multiple uses and interact with different genes in different circumstances. Epistasis and pleiotropy can constrain the freedom of action of selection because tinkering with these genes via selection on one of the traits they affect can have negative effects on the other traits.

However, the system that evolved uncoupled these pleiotropic regulatory proteins from what they regulate, because the protein nnnnniT can remain protected from mutational damage by selection, so it can do its work whenever needed, while mutational change can add, delete, or modify enhancer sequences the regulatory protein recognizes, allowing each use to evolve more independently. This allows considerable flexibility for selection while preserving a relatively stable toolkit, and is another way in which it has not been necessary for each new function to be built de novo by entirely new genes. The indirect, sequestered control of gene function by regulatory elements is another fundamental characteristic of life.

Some of the regulatory processes are subtle, including the way that mammalian X chromosomes are inactivated by being covered with Xist RNA; the competitive binding (or other) mechanism by which the members of globin or Hox gene clusters are sequentially activated; the means by which only one X-linked red or green opsin is expressed in a given retinal photoreceptor; the rearrangement of immunoglobulin or T cell receptor genes and the sequential use of the constant regions as response to infection proceeds; the allelic exclusion by inactivation of the other chromosome for these genes that leads to unique antibodies being produced by a given lymphocyte; and the near total exclusion of all but one olfactory receptor gene from expression in a given olfactory neuron. Posttranscriptional regulation by antisense RNA interference is an additional subtlety that we have mentioned.

A consequence of this layered nature of causation is that a major fraction of biological activity arises from the action of genes that have nothing specific to do with the nature of the final trait to which they contribute. We have referred to this as logically necessary (the trait must be produced) but functionally arbitrary (it doesn't matter how it is produced). Signaling ties the living world together and is another of the general characteristics of life not specifically implied by the fundamental darwinian postulates.

Yet diffusible signals are a kind of arbitrary information-by-agreement. Nothing about an Fgf gene or its receptor need have anything at all to do with the nature of the final trait being made. The same is true with the many transcription factors, second messengers, and the like. Because they are arbitrary they, like codons and enhancer sequences, can form a general-purpose toolkit. However, this is not the same kind of "code," in that there is nothing in Fgf itself that is a stand-in for some trait the way a codon is for an amino acid.

In the last couple of chapters we have taken the notion of functional arbitrariness even further. If a generic toolkit of regulatory factors can in a sense account for all morphologies, it seems true that all of the physically diverse sensory inputs can be perceived by a single set of tools. The diverse functions of perception and central control are achieved by the interaction arrangements among a few types of neural cells. But the cellular properties of neural cells per se have little if anything to do with the nature of an image or smell, with whether one is looking at, touching, or tasting ice or ice cream.

The use of functionally arbitrary processes is deeply a part of life. Neural behavior most compellingly forces attention on the importance of learning how to understand "emergent" traits—that are fundamentally due to the interaction of elements rather than the sum or nature of those elements. How this will relate to or can be achieved by reductionist approaches, with their centuries' head start and long and successful record, or whether entirely new conceptual approaches will be developed, only the future will tell. But functional arbitrariness does seem to imply that we will have to understand many of the traits in life somewhere "above" the level of the gene.

As we saw in Chapters 4 and 5, a problem with genetic mechanisms being so utterly modular is that the genome is saturated with potential functional sequence. As scientists, we understand that function because of decades of experimental investigation carried on from without the organism. Organisms, however, have to figure this out for themselves, and from within. The DNA sequence of a new organism can be interpreted only because it arrives in an appropriate interpretive environment (e.g., mRNA, pH, and so forth in the cell).Again, this is why the distinction between a chicken and an egg is largely a false one: life is continuity. (Various proposed attempts to generate life spontaneously in a test-tube of ingredients may ultimately succeed but will not invalidate this last assertion, because the recipe that will be used will be derived from a knowledge of the nature of current life, that took billions of years to produce from the inside out).

There has been tremendous recent progress in identifying genes (o^ o and processes involved in regulatory aspects of complex traits. But gene lists are not of themselves particularly more informative than ° ° was the classificational analysis of beetles in the 19th century, which is often denigrated from our modern perspective as having been "just" descriptive natural history. Dartboard-like today, regulatory pathway diagrams may ultimately become complete, via tools like expression profiling. Experts in the area are eager to deal with such data (e.g., Davidson 2001; Davidson et al. 2002a; Davidson et al. 2002b), but precedent and even the existing difficulties of understanding known pathway stereotypes suggest to us that how we will deal with the impending information inundation to move from even longer lists to better understanding, is by no means clear. For one thing, each new element adds another source of inter-species, inter-strain, quantitative, or stochastic variation. However one thing even incomplete gene lists have already shown is, again, the ubiquitous use of a few pathways, like Wnt and Fgf signaling and the like. In a sense, this shows how life is a combinatorial molecular phenomenon, another aspect of its fundamentally modular nature— and another challenge to understand emergence.

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